The symptoms come and go unpredictably: persistent patches of scaly skin that shed white flakes excessively, or red and raw rashes that cause pain when clothes rub over them. When they are milder, they’re uncomfortable and distressing; but when they flare, they become debilitating. Even when they’re absent, they leave a constant sense of anxiety over what might trigger their return, which could be anything from a hot day or a bite of seafood, to a stressful time at school or work.
These are some of the difficult everyday realities for patients who live with inflammatory skin diseases: a group of often life-long conditions which includes eczema and psoriasis. The reasons why they come about are complex, but they often appear when something goes wrong with how our skin responds to environmental triggers. Our cellular defenders can overreact by pumping inflammation-boosting molecules in places where they’re not needed, causing new problems instead of fixing old ones.
While many treatments exist for these diseases today, ranging from topical creams to small-molecule inhibitor injections that target the body’s inflammatory systems, these can have their own downsides. Apart from side effects and cost, most provide only a temporary relief from symptoms as they may not fully address the root cause of disease: the dysfunctions in cellular signalling processes that agitate the skin.
At A*STAR Skin Research Labs (A*SRL), a team led by Principal Investigator Kenneth Lay is exploring the possibilities that stem cells offer to tackle inflammatory skin diseases at their root. As the basic building blocks for many other tissues in our body, stem cells have strong regenerative properties that have been used to treat brittle bones, weak hearts and other diseases linked to cellular dysfunction.
As a newly awarded National Research Foundation Fellow, Lay shares some insights from his work in stem cells, the prospects in the field, and his goals as an investigator within the wider skin research community.
What led you to skin stem cell research?
I’ve always been interested in harnessing the regenerative potential of stem cells to treat disease, so I set out to understand the biology of various stem cell types, including mesenchymal, embryonic and induced pluripotent stem cells. During my PhD studies, I wanted to learn more about adult stem cells. They’re the ones responsible for the day-to-day maintenance, renewal and regeneration of various organs of our bodies.
I chose to study skin stem cells in particular, and became fascinated by the skin as an organ: both in the important role it plays in our well-being, and the many diseases related to it that remain unresolved. I thus set up my lab with a vision to harness skin stem cell dynamics for novel therapeutics. My motivation has always been to improve lives through scientific discoveries.
There are many reasons for my focus on inflammatory skin diseases. We don’t really know why we get them, and we can’t really make them go away; they keep recurring despite our best attempts at treating them. Their common manifestations—pain, blisters, itch—can greatly compromise not just a person’s quality of life, but their self-confidence and emotional wellbeing.
A*STAR supported my undergraduate and PhD studies in some of the best universities and laboratories in the world. They allowed me to train with mentors who played pivotal and inspirational roles in my growth as a scientist.
What therapeutic gaps do you hope to address?
Current treatments for inflammatory skin diseases each have their shortfalls. For example, moisturisers can strengthen our skin barrier’s functions, but as we shed skin cells daily, we eventually lose those improved skin layers. In patients with these diseases, the skin stem cells underlying their defective barriers will continue their aberrant crosstalk with immune cells, then differentiate into a new set of defective skin cells, which need another round of treatment… the cycle repeats itself.
On the other hand, there are immunosuppressants which are effective, but because they work by suppressing the immune system, the symptoms often return once you stop treatment, and can be worse than before. Newer immunosuppressants come in the form of costly biologics, which make administration and compliance challenging. Importantly, there are known short-term side effects to these therapies such as drug toxicity and increased risks of infections—and we still don’t know what their long-term effects are.
What exciting prospects do stem cells offer for skin diseases?
Skin stem cells were the first human cells to be grown in the laboratory for clinical use. They can expand rapidly and make sheets of skin in a dish, which can then be used as grafts to save the lives of patients who have lost significant areas of their skin due to burns or genetic disorders.
Beyond these severe conditions, the regenerative potential of skin stem cells has not been fully utilised for some of the more common skin diseases that we face, such as those associated with inflammation, of which eczema and psoriasis are well-known examples. That underuse is because we still don’t know how skin stem cells respond to such disease states. If we can shed more light on these mechanisms, we can start modulating them for more favourable patient outcomes.
What has your lab been working on recently?
One aspect we are working on is dissecting how skin stem cells properly communicate with our immune cells. Our skin is highly potent in initiating and launching an immune attack on harmful things that have penetrated it. But when it loses control of this ability, diseases arise as the crosstalk between skin and immune cells goes into overdrive. We are now looking for ways to alleviate disease by dampening this response.
What impactful experiences have you had in the global skin research community?
I was recently invited to speak at both the inaugural International Societies for Investigative Dermatology conference held in Japan, and the Gordon Research Conference on Epithelial Differentiation and Keratinization held in Spain. I shared with fellow researchers and clinicians our new insights into skin biology that we had obtained through the study of rare genetic skin disorders.
I also had the privilege to be the elected Chair and organiser of the 2023 Gordon Research Seminar, which is an international platform exclusively for postdoctorates and graduate students in skin and epithelial biology to present their work. I ran for the position as a way to contribute back to the community that has helped shape my scientific career. Raising money to run the conference was challenging, especially over the pandemic years, but fortunately the conference was a success, made possible by all the participants who presented their cutting-edge research and are stepping up to be future leaders in the field.
Attending conferences has always been a humbling experience for me. It was a privilege to share my work and get constructive feedback from the community, and also an honour to stay at the forefront of skin research by learning about the latest developments from some of the best laboratories in the world. Being able to reconnect and strengthen relationships with colleagues and friends in the skin research community after the long hiatus caused by the pandemic was an amazing feeling as well.
Since becoming a Principal Investigator, what new perspectives have you gained?
Building up a lab is like starting a new company. First, I need to have a vision; then I need to carve out different paths to realise it. Next, I need to lay the foundation for those paths, which should always rest on sound, creative and rigorous science. Finally, I need to build my team to be able to walk those paths and grow together with me as scientists and future leaders.
To young researchers looking to become Principal Investigators themselves, I would say: train well, build a strong scientific foundation, create a vision, and enjoy the journey.
